4.7 Article

Possible Involvement of the Upregulation of ΔNp63 Expression Mediated by HER2-Activated Aryl Hydrocarbon Receptor in Mammosphere Maintenance

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出版社

MDPI
DOI: 10.3390/ijms232012095

关键词

aryl hydrocarbon receptor; cancer stem cells; breast cancer; Delta Np63

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  1. Ministry of Education, Culture, Sports, Sciences, and Technology of Japan [19K07090]

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This study found that HER2-activated AHR can upregulate the expression of Delta Np63, thus contributing to the maintenance of breast cancer stem cells.
Cancer stem cells (CSCs) contribute to the drug resistance, recurrence, and metastasis of breast cancers. Recently, we demonstrated that HER2 overexpression increases mammosphere formation via the activation of aryl hydrocarbon receptor (AHR). In this study, the objective was to identify the mechanism underlying mammosphere maintenance mediated by HER2 signaling-activated AHR. We compared the chromatin structure of AHR-knockout (AHRKO) HER2-overexpressing MCF-7 (HER2-5) cells with that of wild-type HER2-5 cells; subsequently, we identified TP63, a sternness factor, as a potential target gene of AHR. Delta Np63 mRNA and protein levels were higher in HER2-5 cells than in HER2-5/AHRKO cells. Activation of HER2/HER3 signaling by heregulin treatment increased Delta Np63 mRNA levels, and its induction was decreased by AHR knockdown in HER2-5 cells. The results of the chromatin immunoprecipitation assay revealed an interaction between AHR and the intronic region of TP63, which encodes ANp63. A luciferase reporter gene assay with the intronic region of TP63 showed that AHR expression increased reporter activity. Collectively, our findings suggest that HER2-activated AHR upregulates Delta Np63 expression and that this signaling cascade is involved in CSC maintenance in HER2-expressing breast cancers.

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